Compositions for the treatment of cns-related conditions

ABSTRACT

The invention provides methods for treating CNS-related conditions with amantadine and donepezil, in which the amantadine is in an extended release form, wherein the extended release amantadine formulation provides a change in plasma concentration as a function of time (dC/dT) that is less than 40% of the dC/dT of the same quantity of an immediate release form of amantadine.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/090,396, filed Apr. 4, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/613,220, filed Feb. 3, 2015, which is acontinuation of U.S. patent application Ser. No. 13/863,140, filed Apr.15, 2013, which is a continuation of U.S. patent application Ser. No.13/559,478, filed Jul. 26, 2012, which is a continuation of U.S. patentapplication Ser. No. 13/536,763, filed Jun. 28, 2012, now U.S. Pat. No.8,338,486, issued Dec. 25, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/757,795, filed Apr. 9, 2010, now U.S. Pat. No.8,283,379, issued Oct. 9, 2012, which is a continuation of U.S. patentapplication Ser. No. 11/399,879, filed on Apr. 6, 2006, now U.S. Pat.No. 8,058,291, issued Nov. 15, 2011, which claims priority to andincorporates by reference provisional application 60/669,290, filed onApr. 6, 2005, and is a continuation-in-part of U.S. patent applicationSer. No. 11/285,905, filed on Nov. 22, 2005, now U.S. Pat. No.7,619,007, issued Nov. 17, 2009, which it incorporates by reference inits entirety; U.S. patent application Ser. No. 13/536,763 is also acontinuation-in-part of U.S. application Ser. No. 12/840,132, filed Jul.20, 2010, which is a continuation of Ser. No. 12/512,701, filed Jul. 30,2009, now U.S. Pat. No. 8,168,209, issued May 1, 2009, which is adivision of U.S. application Ser. No. 11/285,905, filed Nov. 22, 2005,now U.S. Pat. No. 7,619,007, issued Nov. 17, 2009, which claims priorityto and incorporates by reference U.S. Provisional Applications60/630,885, filed Nov. 23, 2004, 60/635,365, filed Dec. 10, 2004, and60/701,857, filed Jul. 22, 2005.

FIELD OF THE INVENTION

This invention relates to methods and compositions for treatingCNS-related conditions, such as Alzheimer's disease.

BACKGROUND OF THE INVENTION

Acute and chronic neurological and neuropsychiatric diseases are amongthe leading causes of death, disability, and economic expense in theworld. Presently, Alzheimer's disease is the fourth leading cause ofdeath in the USA. Today there is no known cure for this chronicdegenerative ailment, which directly affects millions of peoplethroughout the world. Other diseases and disorders of the centralnervous system also result in substantial suffering and cost for thoseafflicted by the ailments as well as their families and providers.

Numerous drugs exist in the market today to treat the symptoms or managethe progression of these diseases, but most have modest or limitedefficacy. Frequently, polypharmacy is employed to optimize therapy tothe specific needs of patients at different stages of the disease. Oneof the key challenges in treating these disorders is the high degree ofinterplay amongst the pathways that control both normal and abnormalneuronal functions. The therapeutic management of these functions istypically determined such that the therapeutic effects are maximizedwhile minimizing the debilitating side effects of the therapies. Thiseffort is usually more complex when multiple therapeutics are employed.

Improved therapeutics for treatment of these diseases and disorders areneeded.

SUMMARY OF THE INVENTION

In general, the present invention provides methods and compositions fortreating and preventing CNS-related conditions, such asneurodegenerative conditions (e.g., Alzheimer's disease and Parkinson'sdisease) and pain, by administering to a subject in need thereof acombination that includes an N-Methyl-D-Aspartate receptor (NMDAr)antagonist and a second agent such as acetylcholinesterase inhibitor(ACheI). The administration of the combinations described herein resultsin the alleviation and prevention of symptoms associated with or arisingfrom CNS-related conditions such as Parkinson's disease or Alzheimer'sdisease including, for example, loss of memory, loss of balance,hallucinations, delusions, agitation, withdrawal, depression,communication problems, cognitive loss, personality change, confusionand insomnia. The combinations of the present invention may be used inthe prevention or treatment of CNS-related conditions associated withAlzheimer's disease and may also be helpful for the treatment andprevention of headaches, cerebrovascular diseases, motor neurondiseases, dementias, neurodegenerative diseases, strokes, movementdisorders, ataxic syndromes, disorders of the sympathetic nervoussystem, cranial nerve disorders, myelopathies, traumatic brain andspinal cord injuries, radiation brain injuries, multiple sclerosis,post-meningitis syndrome, prion diseases, myelitic disorders,radiculitis, neuropathies, pain syndromes, axonic brain damage,encephalopathies, chronic fatigue syndrome, psychiatric disorders,glucose dysregulation, and drug dependence.

The NMDAr antagonist, the ACheI, or both agents may be administered inan amount similar to that typically administered to subjects.Optionally, the amount of the NMDAr antagonist, the ACheI, or bothagents may be administered in an amount greater than or less than theamount that is typically administered to subjects. If desired, theamount of the NMDAr antagonist in the pharmaceutical composition is lessthan the amount of NMDAr antagonist required in a unit dose to obtainthe same therapeutic effect for treating or preventing a CNS-relatedcondition when the NMDAr antagonist is administered in the absence ofthe ACheI. Alternatively, the amount of the ACheI in the pharmaceuticalcomposition is less than the amount of the ACheI required in a unit doseto obtain the same therapeutic effect for treating or preventing aCNS-related condition when the ACheI is administered in the absence ofthe NMDAr antagonist. Optionally, the NMDAr antagonist, the ACheI, orboth are present at a higher dose than that typically administered to asubject for a specific condition. For example, the amount of memantine(an NMDAr antagonist) required to positively affect the patient response(inclusive of adverse effects) may be 2.5-80 mg per day rather than thetypical 10-20 mg per day administered for presently approved indicationsi.e. without the improved formulations described herein. A higher doseamount of the NMDAr antagonist in the present invention may be employedwhereas a lower dose of the NMDAr antagonist may be sufficient whencombined with the ACheI to achieve a therapeutic effect in the patient.Optionally, lower or reduced amounts of both the NMDAr antagonist andthe ACheI are used in a unit dose relative to the amount of each agentwhen administered as a monotherapy. In a preferred embodiment, theamount of the NMDAr antagonist in the pharmaceutical composition isequal to or greater than the amount typically administered to a subjectfor a specific condition as a monotherapy and the amount of the ACheI inthe pharmaceutical composition is less than the amount typicallyadministered to a subject for a similar condition.

The invention also provides a pharmaceutical composition that includesan NMDAr antagonist and an ACheI. Optionally, a pharmaceuticallyacceptable carrier is included.

Although compositions comprising a NMDAr antagonist and a second agentsuch as acetylcholinesterase inhibitor (ACheI) have been disclosed (e.g.US 2004/0087658), the problem of providing release of the NMDArantagonist in a desired manner (e.g. in an amount high enough to treatsymptoms or damaging effects of an underlying disease while avoidingundesirable side effects e.g. CNS side effects) when present as acombined therapy has not been addressed. In particular, the presentlyavailable dosage forms of NMDAr antagonists need to be administeredfrequently and require dose escalation at the initiation of therapy toavoid side effects associated with initial exposure to the therapeuticagent. This leads to difficulty in achieving adequate patientcompliance, which is further exacerbated by the complicated dosingschedules of therapeutic modalities used for neurological orneuropsychiatric disorders. This problem has not been addressed in thecontext of providing an NMDAr antagonist as a combined therapy.

Providing a NMDAr antagonist in combination with an ACheI requirescareful formulation and the pharmacokinetic properties of the two agentswill need to be taken into account, for instance to ensure that theamount and rate of release of each of the agents is sufficient for atherapeutic benefit whilst minimizing or avoiding undesired sideeffects. Further, not only do the pharmacokinetic properties of each ofthe drugs (e.g. Tmax, drug half-life etc.) need to be considered, butany interaction between the two agents is a further complicating factor.

In one embodiment of the invention, the NMDAr antagonist, the ACheI, orboth agents may be provided in a controlled or extended release formwith or without an immediate release component in order to maximize thetherapeutic benefit of each, while reducing unwanted side effectsassociated with each.

As used herein, “immediate release formulation” refers to a formulationof an active pharmaceutical ingredient that releases greater than 80percent of the active pharmaceutical ingredient in less than one hour ina USP dissolution method as described herein or by the manufacturer fora commercial product. Typically, the release of the active ingredient inan immediate release formulation is greater than 80 percent in less than30 minutes as in FIGS. 1A and 2A.

When these drugs are provided in an oral form without the benefit ofcontrolled or extended release components, they are released andtransported into the body fluids over a period of minutes to severalhours. Thus, the composition of the invention may contain an NMDArantagonist and a sustained release component, such as a coated sustainedrelease matrix, a sustained release matrix, or a sustained release beadmatrix. In one example, memantine (e.g., 5-80 mg) is formulated withoutan immediate release component using a polymer matrix (e.g., Eudragit),Hydroxypropyl methyl cellulose (HPMC) and a polymer coating (e.g.,Eudragit). Such formulations are comprsessed into solid tablets orgranules. Optionally, a coating such as Opadry® or Surelease® is used.

As used herein the terms “extended release dosage form”, “controlledrelease dosage form” and “sustained release dosage form” and likeexpressions are used interchangeably and include dosage forms where theactive drug substance or substances are released over an extended periodof time. The term “extended” release should be understood in contrast toimmediate release and, in particular, the term indicates that theformulation does not release the full dose of the active ingredientimmediately after dosing. Such extended release dosage forms typicallyallow a reduction in dosing frequency as compared to that presented by aconventional dosage form such as a solution or an immediate releasedosage form. The extended release forms may or may not comprise animmediate release component.

Optionally, the composition described herein is formulated such that atleast one of said NMDAr antagonist or said ACheI has an in vitrodissolution profile less than 70% in one hour, less than 90% in twohours, greater than 40% in six hours, and greater than 85% in 12 hoursas measured using a USP type 2 (paddle) dissolution system at 50 rpm, ata temperature of 37±0.5° with water as a dissolution medium.

As used herein, “C” refers to the concentration of an activepharmaceutical ingredient in a biological sample, such as a patientsample (e.g. blood, serum, and cerebrospinal fluid). The concentrationof the drug in the biological sample may be determined by any standardassay method known in the art. The term “Cmax” refers to the maximumconcentration reached by a given dose of drug in a biological sample.The term “Cmean” refers to the average concentration of the drug in thesample over time. Cmax and Cmean may be further defined to refer tospecific time periods relative to administration of the drug. The timerequired to reach the maximal concentration (“Cmax”) in a particularpatient sample type is referred to as the “Tmax.” The agents of thecombination are administered in formulations that reduce the variabilityof the ratio of the concentrations of the active agents over a period oftime, thereby maximizing the therapeutic benefit while minimizing theside effects.

In a preferred embodiment, the dosage form is provided in a non-doseescalating, twice per day or once per day form. In such cases, theconcentration ramp (or Tmax effect) may be reduced so that the change inconcentration as a function of time (dC/dT) is altered to reduce oreliminate the need to dose escalate the drug. A reduction in dC/dT maybe accomplished, for example, by increasing the Tmax in a relativelyproportional manner. Accordingly, a two-fold increase in the Tmax valuemay reduce dC/dT by approximately a factor of 2. Thus, the NMDArantagonist may be provided so that it is released at a rate that issignificantly reduced over an immediate release (so called IR) dosageform, with an associated delay in the Tmax. The pharmaceuticalcomposition may be formulated to provide a shift in Tmax by 24 hours, 16hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. The associatedreduction in dC/dT may be by a factor of approximately 0.05, 0.10, 0.25,0.5, or at least 0.8. In certain embodiments, this is accomplished byreleasing less than 30%, 50%, 75%, 90%, or 95% of the NMDAr antagonistinto the circulatory or neural system within one hour of suchadministration.

The provision of such non-dose escalating dosage forms are particularlyuseful as they provide the drug at a therapeutically effective amountfrom the onset of therapy further improving patient compliance andadherence and enable the achievement of a therapeutically effectivesteady-state concentration of the drug in a shorter period of time. Thisresults in an earlier indication of effectiveness and increasing theutility of these therapeutic agents for diseases and conditions wheretime is of the essence. Furthermore, the compositions of the presentinvention, by virtue of their design, allow for higher doses of the drugto be safely administered, again increasing the utility of these agentsfor a variety of indications.

If desired, the NMDAr antagonist or the ACheI of the combination isreleased into a subject sample at a slower rate than observed for animmediate release (IR) formulation of the same quantity of theantagonist. The release rate is measured as the dC/dT over a definedperiod within the period of 0 to Tmax for the IR formulation and thedC/dT rate is less than about 80% of the rate for the IR formulation. Insome embodiments, the dC/dT rate is less than about 60%, 50%, 40%, 30%,20% or 10% of the rate for the IR formulation. Similarly, the ACheI mayalso be released into a patient sample at a slower rate than observedfor an IR formulation of the same quantity wherein the release rate ismeasured as the dC/dT over a defined period within the period of 0 toTmax for the IR formulation and the dC/dT rate is less than about 80%,60%, 50%, 40%, 30%, 20%, or 10%, of the rate for the IR formulation ofthe same NMDAr antagonist over the first 1, 2, 4, 6, 8, 10, or 12 hours.

Optionally, the sustained release formulations exhibit plasmaconcentration curves having initial (e.g., from 2 hours afteradministration to 4 hours after administration) slopes less than 75%,50%, 40%, 30%, 20% or 10% of those for an IR formulation of the samedosage of the same NMDAr antagonist. The precise slope for a givenindividual will vary according to the NMDAr antagonist being used, thequantity delivered, or other factors, including, for some activepharmaceutical agents, whether the patient has eaten or not. For otherdoses, e.g., those mentioned above, the slopes vary directly inrelationship to dose.

Using the sustained release formulations described herein, the NMDArantagonist or the ACheI reaches a therapeutically effective steady stateplasma concentration in a subject within the course of the first five,seven, nine, ten, twelve, fifteen, or twenty days of administration. Forexample, the formulations described herein, when administered at asubstantially constant daily dose (e.g., memantine at a dose rangingbetween 15 mg and 80 mg and preferably between 20 and 45 mg) may reach asteady state plasma concentration in approximately 70%, 60%, 50%, 40%,30%, or less of the time required to reach such plasma concentrationwhen using a dose escalating regimen.

The ratio of the concentrations of two agents in a combination isreferred to as the “Cratio,” which may fluctuate as the combination ofdrugs is released, transported into the circulatory system or CNS,metabolized, and eliminated. An objective of the present invention is tostabilize the Cratio for the combinations described herein. In someembodiments, it is preferred to reduce or even minimize the variation inthe Cratio (termed “Cratio,var”). Employing the methods describedherein, the release profiles of each active pharmaceutical ingredientmay be modified to produce nearly constant Cratios, thereby minimizingCratio, var. In cases where the Tmax and T1/2 of the NMDAr antagonistand the ACheI are markedly different, e.g. by a factor of two or more,the desired release profiles will likely be dissimilar in order tominimize the relative variability of the active agents between doses.

The present invention therefore features formulations of combinationsdirected to dose optimization or release modification to reduce adverseeffects associated with separate administration of each agent. Thecombination of the NMDAr antagonist and the ACheI may result in anadditive or synergistic response, as described below.

In all foregoing aspects of the invention, at least 50%, 80, 90%, 95%,or essentially all of the NMDAr antagonist in the pharmaceuticalcomposition may be provided in a controlled release dosage form. In someembodiments, at least 99% of the NMDAr antagonist remains in theextended dosage form one hour following introduction of thepharmaceutical composition into a subject. The NMDAr antagonist may havea C_(max)/C_(mean) of approximately 2, 1.6, 1.5, 1.4, 1.3, 1.2 or less,approximately 2 hours to at least 8, 12, 16, 24 hours after the NMDArantagonist is introduced into a subject. The ACheI may also be providedin a controlled release dosage form. Thus, at least 50%, 60%, 70%, 80%,90%, 95%, or essentially all of the ACheI may be provided as acontrolled release formulation. If provided as such, the ACheI may havea C_(max)/C mean of approximately 2, 1.6, 1.5, 1.4, 1.3, 1.2 or less,approximately 2 hours to at least 6, 8, 12, 16, or 24 hours after theACheI is introduced into a subject.

The active pharmaceutical agents may be administered to the patient in amanner that reduces the variability of the ratio of the concentrationsof the active agents over a period of time, thereby maximizing thetherapeutic benefit while minimizing the side effects. The presentinvention differs from prior studies by providing novel combinations aswell as formulations of combinations directed to dose optimization orrelease modification to reduce adverse effects associated with eachagent.

Optionally, the Cratio,var of the NMDAr antagonist and the ACheI is lessthan 100%, e.g., less than 70%, 50%, 30%, 20%, or 10% after the agentshave reached steady-state conditions. Optionally, the Cratio,var of theNMDAr antagonist and the ACheI is less than 100%, e.g. less than 70%,50%, 30%, 20%, or 10% during the first 24 hours post-administration ofthe agents. In some embodiments, the Cratio,var is less than about 90%(e.g., less than about 75% or 50%) of that for IR administration of thesame active pharmaceutical ingredients over the first 4, 6, 8, or 12hours after administration.

In all foregoing aspects of the invention, the NMDAr antagonist may bean aminoadamantine derivative including memantine(1-amino-3,5-dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), or amantadine (1-amino-adamantane). TheACheI, an acetylcholinesterase inhibitor, may be, e.g.,donepezil/ARICEPT®, rivastigmine/EXELON®, galantamine/REMINYL®,tacrine/COGNEX®, metrifonate, or huperzine-A. Thus, in some embodiments,the NMDAr antagonist is memantine while the ACheI is donepezil,rivastigmine, galantamine, tacrine, metrifonate, or huperzine-A.

In some embodiments, the NMDAr antagonist, the ACheI, or both agents areformulated for oral, intravenous, topical, intranasal, subtopicaltransepithelial, subdermal, or inhalation delivery. Thus, the agentsdescribed herein may be formulated as a suspension, capsule, tablet,suppository, lotion, patch, or device (e.g., a subdermally implantabledelivery device or an inhalation pump). If desired, the NMDA antagonistand the ACheI may be admixed in a single composition. Alternatively, thetwo agents are delivered in separate formulations sequentially, orwithin one hour, two hours, three hours, six hours, 12 hours, or 24hours of each other. If administered separately, the two agents may beadministered by the same or different routes of administration threetimes a day, twice a day, once a day, or even once every two days.Optionally, the two agents are provided together in the form of a kit.Preferably, the NMDAr antagonist and the ACheI are provided in a unitdosage form.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. In the case of conflict, the present Specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting. Allparts and percentages are by weight unless otherwise specified.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a graph showing that the controlled release formulation ofmemantine (Namenda) and sustained release formulations of memantine(NPI-6601, NPI-6701, and NPI-6801). The sustained release formulationscontain 22.5 mg of memantine. These dissolution profiles were obtainedfrom a USP II Paddle system using water as the medium.

FIG. 1B is a graph showing predicted plasma blood levels for 24 hours ofdosing with an immediate release formulation of memantine (Namenda) andsustained release formulations of memantine (NPI-6601, NPI-6701, andNPI-6801), obtained using the Gastro-Plus software package v.4.0.2. Thesustained release formulations contain 22.5 mg of memantine.

FIGS. 2A-2C show dissolution profiles of: FIG. 2A: Sustained Release(SR) Memantine (fast)—Immediate Release (IR) Donepezil (NPI-6170); FIG.2B: SR Memantine (medium)—IR Donepezil (NPI-6270); and FIG. 2C: SRMemantine (slow)—IR Donepezil (NPI-6370).

FIGS. 3A-3C show dissolution profiles of: FIG. 3A: SR Memantine(fast)—SR Donepezil (fast) (NPI-6171); FIG. 3B: SR Memantine (medium)—SRDonepezil (fast) (NPI-6271); and FIG. 3C: SR Memantine (slow)—SRDonepezil (fast) (NPI-6371).

FIGS. 4A-4C show dissolution profiles of: FIG. 4A: SR Memantine(fast)—SR Donepezil (medium) (NPI-6172); FIG. 4B: SR Memantine(medium)—SR Donepezil (medium) (NPI-6272); and FIG. 4C: SR Memantine(slow)—SR Donepezil (medium) (NPI-6372).

FIGS. 5A-5C show dissolution profiles of FIG. 5A: SR Memantine (fast)—SRDonepezil (slow) (NPI-6173); FIG. 5B: SR Memantine (medium)—SR Donepezil(Slow) (NPI-6273); and FIG. 5C: SR Memantine (slow)—SR Donepezil (slow)(NPI-6373).

FIGS. 6A-6E show plasma concentrations obtained using the GastroPlussoftware package v.4.0.2 for the following compositions: FIG. 6A: SRMemantine (fast)—IR Donepezil (NPI-6170); FIG. 6B: SR Memantine(fast)—SR Donepezil (Slow) (NPI-6173; FIG. 6C: SR Memantine (medium)—SRDonepezil (medium) (NPI-6272); FIG. 6D: SR Memantine (Slow) IR Donepezil(NPI-6370; and FIG. 6E: SR Memantine (Slow) SR Donepezil (slow)(NPI-6373).

FIG. 7 shows plasma concentrations obtained using the GastroPlussoftware package v.4.0.2 for an SR Memantine—SR Donepezil forumulation(NPI-6272) and an IR Memantine—IR Donepezil formulation.

FIG. 8 shows pharmacokinetic properties of various IR formulations andSR formulations of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods and compositions for treating orpreventing CNS-related conditions, including psychiatric disorders(e.g., panic syndrome, general anxiety disorder, phobic syndromes of alltypes, mania, manic depressive illness, hypomania, unipolar depression,depression, stress disorders, PTSD, somatoform disorders, personalitydisorders, psychosis, and schizophrenia), and drug dependence (e.g.,alcohol, psychostimulants (e.g., crack, cocaine, speed, and meth),opioids, and nicotine), epilepsy, headache, acute pain, chronic pain,neuropathies, cereborischemia, dementias (including Alzheimer's type),movement disorders, and multiple sclerosis. The combination includes afirst agent that is an NMDAr antagonist and an ACheI (e.g.,donepezil/ARICEPT®, rivastigmine/EXELON®, galantamine/REMINYL®,tacrine/COGNEX®, metrifonate, or huperzine-A). The combination isadministered such that the symptoms associated with CNS-relatedcondition are alleviated or prevented, or alternatively, such thatprogression of the CNS-related condition is reduced. Desirably, eitherof these two agents, or even both agents, is formulated for extendedrelease, thereby providing a concentration over a desired time periodthat is high enough to be therapeutically effective but low enough toreduce or avoid adverse events associated with excessive levels ofeither agent in the subject. Preferably, the compositions of the presentinvention are formulated to provide a concentration ratio variabilityover the dosing interval that is less than that observed or predictedfor formulations where neither component or only one component is in anextended release form.

NMDAr Antagonists

Any NMDAr antagonist can be used in the methods and compositions of theinvention, particularly those that are non-toxic when used in thecombination of the invention. The term “nontoxic” is used in a relativesense and is intended to designate any substance that has been approvedby the United States Food and Drug Administration (“FDA”) foradministration to humans or, in keeping with established regulatorycriteria and practice, is susceptible to approval by the FDA or similarregulatory agency for any country for administration to humans oranimals.

The NMDAr antagonist may be an amino-adamantane compound including, forexample, memantine (1-amino-3,5-dimethyladamantane), rimantadine(1-(1-aminoethyl)adamantane), amantadine (1-amino-adamantane), as wellas pharmaceutically acceptable salts thereof. Memantine is described,for example, in U.S. Pat. Nos. 3,391,142; 5,891,885; 5,919,826; and6,187,338. Amantadine is described, for example, in U.S. Pat. Nos.3,152,180; 5,891,885; 5,919,826; and 6,187,338. Additionalaminoadamantane compounds are described, for example, in U.S. Pat. Nos.4,346,112; 5,061,703; 5,334,618; 5,382,601; 6,444,702; 6,620,845; and6,662,845. All of these patents are incorporated herein by reference.

Further NMDAr antagonists that may be employed include, for example,ketamine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine,riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate,neramexane, spermine, spermidine, levemopamil, dextromethorphan((+)-3-hydroxy-N-methylmorphinan) and its metabolite, dextrorphan((+)-3-hydroxy-N-methylmorphinan), a pharmaceutically acceptable salt orester thereof, or a metabolic precursor of any of the foregoing.

The pharmaceutical composition may be formulated to provide memantine inan amount ranging between 1 and 80 mg/day, 5 and 40 mg/day, or 10 and 20mg/day; amantadine in an amount ranging between 25 and 500 mg/day, 25and 300 mg/day, or 100 and 300 mg/day; or dextromethorphan in an amountranging between 1 and 5000 mg/day, 1 and 1000 mg/day, 100 and 800mg/day, or 200 and 500 mg/day. Pediatric doses will typically be lowerthan those determined for adults. Representative dosing can be found inthe PDR by anyone skilled in the art.

Table 1 shows exemplary the pharmacokinetic properties (e.g., Tmax andT1/2) of memantine, amantadine, and rimantadine.

TABLE 1 Pharmacokinetics and Tox in humans for selected NMDArantagonists Human Tmax PK (t½) in Compound in hrs hrs Normal Dose DoseDependent Tox Memantine 60 3 10-20 mg/day, Dose escalation starting at 5mg required, hallucination Amantadine 15 3 100-300 mg/day HallucinationRimantadine 25 6 100-200 mg/day Insomnia

Acetylcholinesterase Inhibitor

The ACheI of the combination described herein is an acetylcholinesteraseinhibitor (e.g., donepezil/ARICEPT®, rivastigmine/EXELON®,galantamine/REMINYL®, tacrine/COGNEX®, metrifonate, or huperzine-A).

Donepezil, described in U.S. Pat. No. 4,895,841, galantamine, describedin U.S. Pat. No. 4,663,318, and rivastigmine, described in U.S. Pat. No.4,948,807, are all presently approved by the United States FDA for thetreatment of mild to moderate Alzheimer's disease. The use of theseACheIs commonly results in severe nausea, diarrhea, vomiting, and otherside effects, including cardiovascular side effects, most of which aredose dependent. Furthermore, the interruption of therapy typicallyrequires re-titration of the dosing starting at the lowest levels (Am.Fam. Phys. 68(7):136572 (2003)). Ultimately, patients cannot toleratechronic ACheI therapy.

The pharmaceutical composition may be formulated to provide donepezil inan amount ranging between 1 and 10 mg/day, 2 and 5 mg/day, or 2 and 4mg/day; rivastigmine in an amount ranging between 1 and 12 mg/day, 2 and6 mg/day, or 2 and 5 mg/day; or galantamine in an amount ranging between1 and 24 mg/day, 2 and 16 mg/day, or 2 and 12 mg/day. Pediatric doseswill typically be lower than those determined for adults. Representativedosing can be found in the PDR by anyone skilled in the art.

Table 2 shows exemplary the pharmacokinetic properties (e.g., Tmax andT1/2) of donepezil, rivastigmine, galantamine, and Huperzine-A.

TABLE 2 Pharmacokinetics and Tox in humans for selected AcheIs Human PKMain T12 Tmax Dose-Dependent Compound (hrs) (hrs) Normal Dose AdverseEvent ARICEPT ®/ 70 3-4   5-10 mg/day Nausea, diarrhea, Donepezilinsomnia EXELON ®/ 1.5 1-2.5 6-12 mg/day Nausea, vomiting RivastigmineREMINYL ®/ 7 1-2.5 16-24 mg/day Nausea, vomiting, Galantamine anorexiaHUPERZINE-A 4.8 1.3 100-400 μg/day Nausea, hyperactivity, dizziness

Making Controlled Release Formulations

A pharmaceutical composition according to the invention is prepared bycombining a desired NMDAr antagonist or antagonists with one or moreadditional ingredients that, when administered to a subject, causes theNMDAr antagonist to be released at a targeted concentration range for aspecified period of time. The NMDAr antagonist may be provided so thatit is released at a dC/dT that is significantly reduced over an instantrelease (so called IR) dosage form, with an associated delay in theTmax. The pharmaceutical composition may be formulated to provide ashift in Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or atleast 1 hour. The associated reduction in dC/dT may be by a factor ofapproximately 0.05, 0.10, 0.25, 0.5 or at least 0.8. In addition, theNMDAr antagonist may be provided such that it is released at rateresulting in a C_(max)/C_(mean) of approximately 2 or less forapproximately 2 hours to at least 8 hours after the NMDAr antagonist isintroduced into a subject.

In addition, the NMDAr antagonist may be provided such that it isreleased at a rate resulting in a C_(max)/C_(mean) of approximately 2 orless for approximately 2 hours to at least 8 hours after the NMDArantagonist is introduced into a subject. Optionally, the sustainedrelease formulations exhibit plasma concentration curves having initial(e.g., from 2 hours after administration to 4 hours afteradministration) slopes less than 75%, 50%, 40%, 30%, 20% or 10% of thosefor an IR formulation of the same dosage of the same NMDAr antagonist.The precise slope for a given individual will vary according to theNMDAr antagonist being used or other factors, including whether thepatient has eaten or not. For other doses, e.g., those mentioned above,the slopes vary directly in relationship to dose. The determination ofinitial slopes of plasma concentration is described, for example, byU.S. Pat. No. 6,913,768, hereby incorporated by reference.

Optionally, the composition described herein is formulated such theNMDAr antagonist has an in vitro dissolution profile less than 70% inone hour, less than 90% in two hours, greater than 40% in six hours, andgreater than 85% in 12 hours as measured using a USP type 2 (paddle)dissolution system at 50 rpm, at a temperature of 37±0.5° with water asa dissolution medium.

Desirably, the compositions described herein have an in vitrodissolution profile that is substantially identical to the dissolutionprofile shown for the formulations shown in FIGS. 1A and 2-5 and, uponadministration to a subject at a substantially constant daily dose,achieves a plasma concentration profile that is substantially identicalto those shown in FIGS. 1B,6, and 7.

A release profile, i.e., the extent of release of the NMDAr antagonistover a desired time, can be conveniently determined for a given time bycalculating the C_(max)/C_(mean) for a desired time range. For example,the NMDAr antagonist can be provided so that it is released atC_(max)/C_(mean) of approximately 2 or less for approximately 2 hours toat least 6 hours after the NMDAr antagonist is introduced into asubject. One of ordinary skill in the art can prepare combinations witha desired release profile using the NMDAr antagonists and formulationmethods described below.

Optionally, the ACheI may also be prepared as a controlled releaseformulation as described above for the NMDAr antagonist.

Using the formulations described herein, therapeutic levels may beachieved while minimizing debilitating side-effects that are usuallyassociated with immediate release formulations. Furthermore, as a resultof the reduction in the time to obtain peak plasma level and thepotentially extended period of time at the therapeutically effectiveplasma level, the dosage frequency may be reduced to, for example, onceor twice daily dosage, thereby improving patient compliance andadherence. For example, side effects including psychosis and cognitivedeficits associated with the administration of NMDAr antagonists may belessened in severity and frequency through the use of controlled-releasemethods that shift the Tmax to longer times, thereby reducing the dC/dTof the drug. Reducing the dC/dT of the drug not only increases Tmax, butalso reduces the drug concentration at Tmax and reduces the Cmax/Cmeanratio providing a more constant amount of drug to the subject beingtreated over a given period of time and reducing adverse eventsassociated with dosing. With regards to the ACheI, the lower dC/dT andCmean will result in a lower incidence of cardiovascular or gastric sideeffects and other adverse events.

In addition to the specific combinations disclosed herein, combinationsmade of a first NMDAr antagonist and the ACheI may be identified bytesting the ability of a test combination of a selected NMDAr antagonistand one or more ACheIs to lessen the symptoms of a CNS-related disorder.Preferred combinations are those in which a lower therapeuticallyeffective amount of the NMDAr antagonist and/or the ACheI is presentrelative to the same amount of the NMDAr antagonist and/or the ACheIrequired to obtain the same effect when each agent is tested separately.

The amounts and ratios of the NMDAr antagonist and the ACheI areconveniently varied to maximize the therapeutic benefit and minimize thetoxic or safety concerns. The NMDAr antagonist may range between 20% and200% of its normal effective dose and the ACheI may range between 20% to200% of its normal effective dose. The precise ratio may vary accordingto the condition being treated. In one example, the amount of memantineranges between 2.5 and 80 mg per day and the amount of donepezil rangesbetween 1 and 20 mg/day.

When the memantine is in a controlled-release form, the preferred dosagerange is 10 mg to 80 mg per day; daily doses of about 22.5, 27.5, 32.5,37.5, 42.5, 47.5, 52.5, 57.5, 62.5, 67.5, 72.5, 77.5 mg are particularlypreferred. When the donepezil is in a controlled-release form, thepreferred dosage range 1 mg to 10 mg per day; daily doses of about 1.0,1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8,4.0, 4.2, 4.4, 4.6, 4.8, 5.0 mg per day are particularly preferred. In aparticularly preferred embodiment the memantine dose is 30-45 mg perday, taken in combination with a donepezil dose of 2-4 mg/day,administered as a single dosage form, with no dose escalation over time.The combination dosage form preferably has sustained releaseformulations for memantine, donepezil or both, such that the dissolutionprofile of the two drugs in the combination tablet are “matched”,especially with regards to the Tmax, dC/dT (normalized for the dose ofNMDAr antagonist and ACheI) in a human. For memantine and donepezil,which have similar pharmacokinetic properties, in vitro dissolutionprofiles will also be similar.

In a preferred embodiment of this invention, memantine and donepezil areformulated into beads or pellets (as described herein) withsubstantially similar dissolution profiles. More preferably, beads orpellets of memantine are prepared with a dissolution profiles similar tothat shown for memantine in FIG. 4B and, separately, beads or pellets ofdonepezil are prepared with a dissolution profile similar to that shownfor donepezil in the same figure. The preferred pellets areapproximately 0.4 mg each and contain approximately 60 μg memantine ordonepezil and easily characterized by known methods. The beads may befilled into gelatin capsules by mass or number to achieve the preferredmass of memantine of 30-45 mg per capsules and donepezil of 2-4 mg percapsule. For example, a 42 mg memantine 3.6 mg donepezil combination maybe prepared by combining 700 memantine beads with 60 donepezil beads ineach capsule, equivalent to 280 mg memantine beads plus 24 mg donepezilbeads per capsule.

Additionally, different release profiles for each active pharmaceuticalingredient may be prepared and combined in prescribed ratios to adjustthe release profile for each of the ingredients, enabling the more rapiddevelopment of formulations for development purposes or specializedformulations for individual products.

For a specified range a physician or other appropriate healthprofessional will typically determine the best dosage for a givenpatient, according to his sex, age, weight, pathological state, andother parameters. In some cases, it may be necessary to use dosageoutside of the range stated in pharmaceutical packaging insert to treata subject. Those cases will be apparent to the prescribing physician orveterinarian.

In some embodiments, the combinations of the invention achievetherapeutic levels while minimizing debilitating side-effects that areusually associated with immediate release formulations. Furthermore, asa result of the delay in the time to obtain peak plasma level and thepotentially extended period of time at the therapeutically effectiveplasma level, the dosage frequency may be reduced to, for example, onceor twice daily dosage, thereby improving patient compliance andadherence.

Accordingly, the combination of the invention allows the NMDArantagonist and the ACheI to be administered in a combination thatimproves efficacy and avoids undesirable side effects of both drugs. Forexample, side effects including psychosis and cognitive deficitsassociated with the administration of NMDAr antagonists may be lessenedin severity and frequency through the use of controlled-release methodsthat shift the Tmax to longer times, thereby reducing the dC/dT of thedrug. Reducing the dC/dT of the drug not only increases Tmax, but alsoreduces the drug concentration at Tmax and reduces the Cmax/Cmean ratioproviding a more constant amount of drug to the subject being treatedover a given period of time and reducing adverse events associated withdosing. Similarly, side effects associated with the use of ACheIs mayalso be reduced in severity and frequency through controlled releasemethods.

In certain embodiments, the combinations provide additive effects.Additivity is achieved by combining the active agents without requiringcontrolled release technologies. In other embodiments, particularly whenthe pharmacokinetic profiles of the combined active pharmaceuticalingredients are dissimilar, controlled release formulations optimize thepharmacokinetics of the active pharmaceutical agents to reduce thevariability of the Cratio over time. Reduction of Cratio variabilityover a defined time period enables a concerted effect for the agentsover that time, maximizing the effectiveness of the combination. TheCratio variability (“Cratio.var”) is defined as the standard deviationof a series of Cratios taken over a given period of time divided by themean of those Cratios multiplied by 100%. The Cratio for the controlledrelease formulation of drugs with significantly differentpharmacokinetic properties is more consistent than for the IRadministration of the same drugs over any significant time period,including shortly after administration and at steady state.

Modes of Administration

The combination of the invention may be administered in either a localor systemic manner or in a depot or sustained release fashion. The twoagents may be delivered in an oral, transdermal or intranasalformulation. In a preferred embodiment, the NMDAr antagonist, the ACheIof the combination, or both agents may be formulated to providecontrolled, extended release (as described herein). For example, apharmaceutical composition that provides controlled release of the NMDArantagonist, the ACheI, or both may be prepared by combining the desiredagent or agents with one or more additional ingredients that, whenadministered to a subject, causes the respective agent or agents to bereleased at a targeted rate for a specified period of time. The twoagents are preferably administered in a manner that provides the desiredeffect from the first and second agents in the combination. Optionally,the first and second agents are admixed into a single formulation beforethey are introduced into a subject. The combination may be convenientlysub-divided in unit doses containing appropriate quantities of the firstand second agents. The unit dosage form may be, for example, a capsuleor tablet itself or it can be an appropriate number of such compositionsin package form. The quantity of the active ingredients in the unitdosage forms may be varied or adjusted according to the particular needof the condition being treated.

Alternatively, the NMDAr antagonist and the ACheI of the combination maynot be mixed until after they are introduced into the subject. Thus, theterm “combination” encompasses embodiments where the NMDAr antagonistand the ACheI are provided in separate formulations and are administeredsequentially. For example, the NMDAr antagonist and the ACheI may beadministered to the subject separately within 2 days, 1 day, 18 hours,12 hours, one hour, a half hour, 15 minutes, or less of each other. Eachagent may be provided in multiple, single capsules or tablets that areadministered separately to the subject. Alternatively, the NMDArantagonist and the ACheI are separated from each other in apharmaceutical composition such that they are not mixed until after thepharmaceutical composition has been introduced into the subject. Themixing may occur just prior to administration to the subject or well inadvance of administering the combination to the subject.

If desired, the NMDAr antagonist and the ACheI may be administered tothe subject in association with other therapeutic modalities, e.g.,drug, surgical, or other interventional treatment regimens. Accordingly,the combination described herein may be administered simultaneously orwithin 14 days, 7 days, 5 days, 3 days, one day, 12 hours, 6 hours, 3hours, or one hour of additional therapeutic modalities. Where thecombination includes a non-drug treatment, the non-drug treatment may beconducted at any suitable time so long as a beneficial effect from theco-action of the combination and the other therapeutic modalities isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the non-drug treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

The preparation of pharmaceutical or pharmacological compositions areknown to those of skill in the art in light of the present disclosure.General techniques for formulation and administration are found in“Remington: The Science and Practice of Pharmacy, Twentieth Edition,”Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules,pills, powders, granules, dragées, gels, slurries, ointments, solutionssuppositories, injections, inhalants and aerosols are examples of suchformulations.

In some embodiments, the first agent and second agent of the combinationdescribed herein are provided within a single or separate pharmaceuticalcompositions. “Pharmaceutically or Pharmacologically Acceptable”includes molecular entities and compositions that do not produce anadverse, allergic or other untoward reaction when administered to ananimal, or a human, as appropriate. “Pharmaceutically AcceptableCarrier” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents for pharmaceuticalactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active ingredient,its use in the therapeutic compositions is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions.“Pharmaceutically Acceptable Salts” include acid addition salts andwhich are formed with inorganic acids such as, for example, hydrochloricor phosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

Formulations for Oral Administration

Combinations can be provided as pharmaceutical compositions that areoptimized for particular types of delivery. For example, pharmaceuticalcompositions for oral delivery are formulated using pharmaceuticallyacceptable carriers that are well known in the art and described furtherbelow. The carriers enable the agents in the combination to beformulated, for example, as a tablet, pill, capsule, solution,suspension, powder, liquid, or gel for oral ingestion by the subject.

The NMDAr antagonist, the ACheI of the invention, or both agents may beprovided in a controlled, extended release form. In one example, atleast 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of theNMDAr antagonist is provided in an extended release dosage form. Arelease profile, i.e., the extent of release of the NMDAr antagonist orthe ACheI over a desired time, may be conveniently determined for agiven time by calculating the C_(max)/C_(mean) for a desired time rangeto achieve a given acute or chronic steady state serum concentrationprofile. Thus, upon the administration to a subject (e.g., a mammal suchas a human), the NMDAr antagonist has a Cmax/Cmean of approximately 2.5,2, 1.5, or 1.0 approximately 1, 1.5, 2 hours to at least 6, 8, 9, 12,18, 21, or 24 hours following such administration. If desired, therelease of the NMDAr antagonist may be monophasic or multiphasic (e.g.,biphasic). Moreover, the ACheI may be formulated as an extended releasecomposition, having a C_(max)/C_(mean) of approximately 2.5, 2, 1.5, or1.0, approximately 1, 1.5, 2 hours to at least 6, 8, 9, 12, 18, 21, or24 hours following administration to a subject. One of ordinary skill inthe art can prepare combinations with a desired release profile usingthe NMDAr antagonists and the ACheI and formulation methods known in theart or described below.

As shown in Tables 1 and 2, the pharmacokinetic half-lives of the drugsof both classes vary from about 1.5 hours to 70 hours. Thus, suitableformulations may be conveniently selected to achieve nearly constantconcentration profiles over an extended period (preferably from 8 to 24hours) thereby maintaining both agents in a constant ratio andconcentration for optimal therapeutic benefits for both acute andchronic administration. Preferred Cratio,var values may be less thanabout 30%, 50%, 75%, 90% of those for IR administration of the sameactive pharmaceutical ingredients over the first 4, 6, 8, or 12 hoursafter administration. Preferred Cratio,var values are less than about100%, 70%, 50%, 30%, 20%, 10%.

Formulations that deliver this constant, measurable profile also allowone to achieve a monotonic ascent from an acute ratio to a desiredchronic ratio for drugs with widely varying elimination half-lives.Compositions of this type and methods of treating patients with thesecompositions are embodiments of the invention. Numerous ways exist forachieving the desired release profiles, as exemplified below.

In some embodiments, the first agent and second agent of the combinationdescribed herein are provided within a single or separate pharmaceuticalcompositions. “Pharmaceutically or Pharmacologically Acceptable”includes molecular entities and compositions that do not produce anadverse, allergic or other untoward reaction when administered to ananimal, or a human, as appropriate. “Pharmaceutically AcceptableCarrier” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents for pharmaceuticalactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active ingredient,its use in the therapeutic compositions is contemplated. Supplementaryactive ingredients can also be incorporated into the compositions.“Pharmaceutically Acceptable Salts” include acid addition salts andwhich are formed with inorganic acids such as, for example, hydrochloricor phosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

Suitable methods for preparing combinations in which the first agent,ACheI, or both agents are provided in extended release-formulationsinclude those described in U.S. Pat. No. 4,606,909 (hereby incorporatedby reference). This reference describes a controlled release multipleunit formulation in which a multiplicity of individually coated ormicroencapsulated units are made available upon disintegration of theformulation (e.g., pill or tablet) in the stomach of the animal (see,for example, column 3, line 26 through column 5, line 10 and column 6,line 29 through column 9, line 16). Each of these individually coated ormicroencapsulated units contains cross-sectionally substantiallyhomogenous cores containing particles of a sparingly soluble activesubstance, the cores being coated with a coating that is substantiallyresistant to gastric conditions but which is erodable under theconditions prevailing in the small intestine.

The combination may alternatively be formulated using the methodsdisclosed in U.S. Pat. No. 4,769,027, for example. Accordingly, extendedrelease formulations involve prills of pharmaceutically acceptablematerial (e.g., sugar/starch, salts, and waxes) may be coated with awater permeable polymeric matrix containing an NMDAr antagonist and nextovercoated with a water-permeable film containing dispersed within it awater soluble particulate pore forming material.

One or both agents of the combination may additionally be prepared asdescribed in U.S. Pat. No. 4,897,268, involving a biocompatible,biodegradable microcapsule delivery system. Thus, the NMDAr antagonistmay be formulated as a composition containing a blend of free-flowingspherical particles obtained by individually microencapsulatingquantities of memantine, for example, in different copolymer excipientswhich biodegrade at different rates, therefore releasing memantine intothe circulation at a predetermined rates. A quantity of these particlesmay be of such a copolymer excipient that the core active ingredient isreleased quickly after administration, and thereby delivers the activeingredient for an initial period. A second quantity of the particles isof such type excipient that delivery of the encapsulated ingredientbegins as the first quantity's delivery begins to decline. A thirdquantity of ingredient may be encapsulated with a still differentexcipient which results in delivery beginning as the delivery of thesecond quantity beings to decline. The rate of delivery may be altered,for example, by varying the lactide/glycolide ratio in apoly(D,L-lactide-co-glycolide) encapsulation. Other polymers that may beused include polyacetal polymers, polyorthoesters, polyesteramides,polycaprolactone and copolymers thereof, polycarbonates,polyhydroxybuterate and copolymers thereof, polymaleamides,copolyaxalates and polysaccharides.

In one embodiment of the invention, the NMDAr antagonist, the ACheI, orboth agents may be provided in a controlled or extended release formwith or without an immediate release component in order to maximize thetherapeutic benefit of each, while reducing unwanted side effectsassociated with each. When these drugs are provided in an oral formwithout the benefit of controlled or extended release components, theyare released and transported into the body fluids over a period ofminutes to several hours. Thus, the composition of the invention maycontain an NMDAr antagonist and a sustained release component, such as acoated sustained release matrix, a sustained release matrix, or asustained release bead matrix. In one example, memantine (e.g., 5-80 mg)is formulated without an immediate release component using a polymermatrix (e.g., Eudragit), Hydroxypropyl methyl cellulose (HPMC) and apolymer coating (e.g., Eudragit). Such formulations are compressed intosolid tablets or granules or formed into pellets for capsules ortablets. Optionally, a coating such as Opadry® or Surelease® is used.

Separately prepared pellets, preferably release controlling pellets,combined in any manner provide the flexibility of making ratios of NMDArantagonist to ACheI containing compositions ranging from 0.1:100 to100:0.1, more preferably from 1:100 to 100:1, most preferably 1:10 to10:1 by mass or by numbers of pellets (see Example 7), and at thedesired release profiles for each of the active ingredients. Optionally,the NMDAr antagonist, the ACheI, or both agents are prepared using theOROS® technology, described for example, in U.S. Pat. Nos. 6,919,373,6,923,800, 6,929,803, 6,939,556, and 6,930,128, all of which are herebyincorporated by reference. This technology employs osmosis to provideprecise, controlled drug delivery for up to 24 hours and can be usedwith a range of compounds, including poorly soluble or highly solubledrugs. OROS® technology can be used to deliver high drug doses meetinghigh drug loading requirements. By targeting specific areas of thegastrointestinal tract, OROS® technology may provide more efficient drugabsorption and enhanced bioavailability. The osmotic driving force ofOROS® and protection of the drug until the time of release eliminate thevariability of drug absorption and metabolism often caused by gastric pHand motility

Alternatively, the combination may be prepared as described in U.S. Pat.No. 5,395,626 features a multilayered controlled release pharmaceuticaldosage form. The dosage form contains a plurality of coated particleswherein each has multiple layers about a core containing an NMDArantagonist and/or the ACheI whereby the drug containing core and atleast one other layer of drug active is overcoated with a controlledrelease barrier layer therefore providing at least two controlledreleasing layers of a water soluble drug from the multilayered coatedparticle.

By way of example, extended release oral formulation can be preparedusing additional methods known in the art. For example, a suitableextended release form of the either active pharmaceutical ingredient orboth may be a matrix tablet composition. Suitable matrix formingmaterials include, for example, waxes (e.g., carnauba, bees wax,paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols),oils, hardened oils or fats (e.g., hardened rapeseed oil, castor oil,beef tallow, palm dil, and soya bean oil), and polymers (e.g.,hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyethylene glycol). Other suitable matrix tablettingmaterials are microcrystalline cellulose, powdered cellulose,hydroxypropyl cellulose, ethyl cellulose, with other carriers, andfillers. Tablets may also contain granulates, coated powders, orpellets. Tablets may also be multi-layered. Multi-layered tablets areespecially preferred when the active ingredients have markedly differentpharmacokinetic profiles. Optionally, the finished tablet may be coatedor uncoated.

The coating composition typically contains an insoluble matrix polymer(approximately 15-85% by weight of the coating composition) and a watersoluble material (e.g., approximately 15-85% by weight of the coatingcomposition). Optionally an enteric polymer (approximately 1 to 99% byweight of the coating composition) may be used or included. Suitablewater soluble materials include polymers such as polyethylene glycol,hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such assugars (e.g., lactose, sucrose, fructose, mannitol and the like), salts(e.g., sodium chloride, potassium chloride and the like), organic acids(e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), andmixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose, acetate succinate, hydroxypropyl methyl cellulose, phthalate,polyvinyl acetate phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, shellac, zein, and polymethacrylates containingcarboxyl groups.

The coating composition may be plasticised according to the propertiesof the coating blend such as the glass transition temperature of themain agent or mixture of agents or the solvent used for applying thecoating compositions. Suitable plasticisers may be added from 0 to 50%by weight of the coating composition and include, for example, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, acetylated citrate esters, dibutylsebacate, and castor oil.If desired, the coating composition may include a filler. The amount ofthe filler may be 1% to approximately 99% by weight based on the totalweight of the coating composition and may be an insoluble material suchas silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch,powdered cellulose, MCC, or polacrilin potassium.

The coating composition may be applied as a solution or latex in organicsolvents or aqueous solvents or mixtures thereof. If solutions areapplied, the solvent may be present in amounts from approximate by25-99% by weight based on the total weight of dissolved solids. Suitablesolvents are water, lower alcohol, lower chlorinated hydrocarbons,ketones, or mixtures thereof. If latexes are applied, the solvent ispresent in amounts from approximately 25-97% by weight based on thequantity of polymeric material in the latex. The solvent may bepredominantly water.

The pharmaceutical composition described herein may also include acarrier such as a solvent, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Pharmaceutically acceptable salts can also be used inthe composition, for example, mineral salts such as hydrochlorides,hydrobromides, phosphates, or sulfates, as well as the salts of organicacids such as acetates, proprionates, malonates, or benzoates. Thecomposition may also contain liquids, such as water, saline, glycerol,and ethanol, as well as substances such as wetting agents, emulsifyingagents, or pH buffering agents. Liposomes, such as those described inU.S. Pat. No. 5,422,120, WO 95/13796, WO 91/14445, or EP 524,968 B1, mayalso be used as a carrier.

Additional methods for making controlled release formulations aredescribed in, e.g., U.S. Pat. Nos. 5,422,123; 5,601,845; 5,912,013; and6,194,000, all of which are hereby incorporated by reference.

Formulations for Other Routes of Administration

Alternatively, the compositions of the present invention may beadministered transdermally. Preparation for delivery in a transdermalpatch can be performed using methods also known in the art, includingthose described generally in, e.g., U.S. Pat. Nos. 5,186,938; 6,183,770;4,861,800; 4,284,444 and WO 89/09051. A patch is a particularly usefulembodiment in cases where the therapeutic agent has a short half-life orrequires reduction in dC/dT. Patches can be made to control the releaseof skin-permeable active ingredients over a 12 hour, 24 hour, 3 day, and7 day period. In one example, a 2-fold daily excess of an NMDArantagonist is placed in a non-volatile fluid along with the opiatenarcotic agent, non-steroidal anti-inflammatory agent, or anesthetic.Given the amount of the agents employed herein, a preferred release willbe from 12 to 72 hours.

Transdermal preparations of this form will contain from 1% to 50% activeingredients. The compositions of the invention are provided in the formof a viscous, non-volatile liquid. Preferably, both members of thecombination will have a skin penetration rate of at least 10⁻⁹mole/cm²/hour. At least 5% of the active material will flux through theskin within a 24 hour period. The penetration through skin of specificformulations may be measures by standard methods in the art (forexample, Franz et al., J. Invest. Derm. 64:194-195 (1975)).

Pharmaceutical compositions containing the NMDAr antagonist and/or ACheIof the combination may also be delivered in an aerosol spray preparationfrom a pressurized pack, a nebulizer or from a dry powder inhaler.Suitable propellants that can be used in a nebulizer include, forexample, dichlorodifluoro-methane, trichlorofluoromethane,dichlorotetrafluoroethane and carbon dioxide. The dosage may bedetermined by providing a valve to deliver a regulated amount of thecompound in the case of a pressurized aerosol.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral,intranasal or respiratory route for local or systemic effect.Compositions in preferably sterile pharmaceutically acceptable solventsmay be nebulized by use of inert gases. Nebulized solutions may bebreathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask, tent or intermittent positive pressurebreathing machine. Solution, suspension or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

In some embodiments, for example, the composition may be deliveredintranasally to the cribriform plate rather than by inhalation to enabletransfer of the active agents through the olfactory passages into theCNS and reducing the systemic administration. Devices used for thisroute of administration are included in U.S. Pat. No. 6,715,485.Compositions delivered via this route may enable increased CNS dosing orreduced total body burden reducing systemic toxicity risks associatedwith certain drugs.

Additional formulations suitable for other modes of administrationinclude rectal capsules or suppositories. For suppositories, traditionalbinders and carriers may include, for example, polyalkylene glycols ortriglycerides; such suppositories may be formed from mixtures containingthe active ingredient in the range of 0.5% to 10%, preferably 1%-2%.

The combination may optionally be formulated for delivery in a vesselthat provides for continuous long-term delivery, e.g., for delivery upto 30 days, 60 days, 90 days, 180 days, or one year. For example thevessel can be provided in a biocompatible material such as titanium.Long-term delivery formulations are particularly useful in subjects withchronic conditions, for assuring improved patient compliance, and forenhancing the stability of the combinations. Formulations for continuouslong-term delivery are provided in, e.g., U.S. Pat. Nos. 6,797,283;6,764,697; 6,635,268, and 6,648,083.

If desired, the agents may be provided in a kit/as a combinedpreparation. The kit/combined preparation can additionally includeinstructions for use. In some embodiments, the kit/combined preparationincludes in one or more containers the NMDAr antagonist and, separately,in one or more containers, the ACheI described herein. The NMDArantagonist and ACheI may be mixed together prior to administration ormay be administered separately to the subject. Where they areadministered separately to the patient they may be administered at thesame time as separate formulations, at different times and overdifferent periods of time, which may be separate from one another oroverlapping. The NMDAr antagonist and ACheI may be administered in anyorder.

In other embodiments, the kit/combined preparation provides acombination with the NMDAr antagonist and the ACheI mixed in one or morecontainers. The kits/combined preparations include a therapeuticallyeffective dose of an agent for treating dementia or other CNS-relatedcondition.

Preparation of a pharmaceutical composition for delivery in asubdermally implantable device can be performed using methods known inthe art, such as those described in, e.g., U.S. Pat. Nos. 3,992,518;5,660,848; and 5,756,115.

Indications Suitable for Treatment with the Combination

Any subject experiencing or at risk of experiencing a CNS-relateddisorder including dementia (e.g., Alzheimer's disease, Parkinson'sdisease, Picks disease, fronto-temporal dementia, vascular dementia,normal pressure hydrocephalus, HD, and MCI), neuro-related conditions,dementia-related conditions, such as epilepsy, seizure disorders, acutepain, chronic pain, chronic neuropathic pain may be treated using thecombinations and methods described herein. Epileptic conditions includecomplex partial, simple partial, partials with secondary generalization,generalized—including absence, grand mal (tonic clonic), tonic, atonic,myoclonic, neonatal, and infantile spasms. Additional specific epilepsysyndromes are juvenile myoclonic epilepsy, Lennox-Gastaut, mesialtemporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressiveepilepsy with mental retardation, and progressive myoclonic epilepsy.The combinations of the invention are also useful for the treatment andprevention of pain caused by disorders including cerebrovasculardisease, motor neuron diseases (e.g., ALS, Spinal motor atrophies,Tay-Sach's, Sandoff disease, familial spastic paraplegia),neurodegenerative diseases (e.g., familial Alzheimer's disease,prion-related diseases, cerebellar ataxia, Friedrich's ataxia, SCA,Wilson's disease, RP, ALS, Adrenoleukodystrophy, Menke's Sx, cerebralautosomal dominant arteriopathy with subcortical infarcts (CADASIL);spinal muscular atrophy, familial ALS, muscular dystrophies, CharcotMarie Tooth diseases, neurofibromatosis, von-Hippel Lindau, Fragile X,spastic paraplesia, psychiatric disorders (e.g., panic syndrome, generalanxiety disorder, phobic syndromes of all types, mania, manic depressiveillness, hypomania, unipolar depression, depression, stress disorders,PTSD, somatoform disorders, personality disorders, psychosis, andschizophrenia), and drug dependence (e.g., alcohol, psychostimulants(eg, crack, cocaine, speed, meth), opioids, and nicotine), Tuberoussclerosis, and Wardenburg syndrome), strokes (e.g, thrombotic, embolic,thromboembolic, hemmorhagic, venoconstrictive, and venous), movementdisorders (e.g., PD, dystonias, benign essential tremor, tardivedystonia, tardive dyskinesia, and Tourette's syndrome), ataxicsyndromes, disorders of the sympathetic nervous system (e.g., ShyDrager, Olivopontoicerebellar degeneration, striatonigral degenration,PD, HD, Gullian Barre, causalgia, complex regional pain syndrome types Iand II, diabetic neuropathy, and alcoholic neuropathy), Cranial nervedisorders (e.g., Trigeminal neuropathy, trigeminal neuralgia, Menier'ssyndrome, glossopharangela neuralgia, dysphagia, dysphonia, and cranialnerve palsies), myelopethies, traumatic brain and spinal cord injury,radiation brian injury, multiple sclerosis, Post-menengitis syndrome,prion diseases, myelities, radiculitis, neuropathies (e.g.,Guillian-Barre, diabetes associated with dysproteinemias,transthyretin-induced neuropathies, neuropathy associated with HIV,neuropathy associated with Lyme disease, neuropathy associated withherpes zoster, carpal tunnel syndrome, tarsal tunnel syndrome,amyloid-induced neuropathies, leprous neuropathy, Bell's palsy,compression neuropathies, sarcoidosis-induced neuropathy, polyneuritiscranialis, heavy metal induced neuropathy, transition metal-inducedneuropathy, drug-induced neuropathy), axonic brain damage,encephalopathies, and chronic fatigue syndrome. All of the abovedisorders may be treated with the combinations and methods describedherein.

Administration of the Compositions

Immediate release formulations of memantine (e.g., Namenda) aretypically administered at low doses (e.g., 5 mg/day) and progressivelyadministered at increasing frequency and dose over time to reach asteady state serum concentration that is therapeutically effective.According to the manufacturer's recommendation, Namenda, an immediaterelease formulation of memantine, is first administered to subjects at adose of 5 mg per day. After a period of time, subjects are administeredwith this dose twice daily. Subjects are next administered with a 5 mgand 10 mg dosing per day and finally administered with 10 mg Namendatwice daily. Using this approved dosing regimen, a therapeuticallyeffective steady state serum concentration may be achieved within aboutthirty days following the onset of therapy. Using a sustained releaseformulation (at a constant daily dose of 22.5 mg, for example), atherapeutically effective steady state concentration may be achievedsubstantially sooner, without using a dose escalating regimen. Suchconcentration is predicted to be achieved within 13 days of the onset oftherapy. Furthermore, the slope during each absorption period for thesustained release formulation is less (i.e. not as steep) as the slopefor Namenda. Accordingly, the dC/dt of the sustained release formulationis reduced relative to the immediate release formulation even though thedose administered is larger than for the immediate release formulation.Based on this model, a sustained release formulation of memantine may beadministered to a subject in an amount that is approximately the fullstrength dose (or that effectively reaches a therapeutically effectivedose) from the onset of therapy and throughout the duration oftreatment. Accordingly, a dose escalation would not be required.Similarly, the controlled release methods described herein may beemployed to reduce the dC/dT for other NMDAr antagonists or ACheIsenabling the administration of the combinations without the requirementfor dose escalation.

Treatment of a subject with the combination may be monitored usingmethods known in the art. The efficacy of treatment using thecombination is preferably evaluated by examining the subject's symptomsin a quantitative way, e.g., by noting a decrease in the frequency ofadverse symptoms, behaviors, or attacks, or an increase in the time forsustained worsening of symptoms. In a successful treatment, thesubject's status will have improved (i.e., frequency of relapses willhave decreased, or the time to sustained progression will haveincreased).

The invention will be illustrated in the following non-limitingexamples.

Example 1 In Vivo Method for Determining Optimal Steady-StateConcentration Ratio (C_(ratio,ss))

A dose ranging study is performed using, for example, the dementia model(APP23 mouse model described by Van Dam et al. (See Psychopharmacology2005, 180(1):177-190), or the Tg2576 model described by Dong et al(Psychopharmacology 2005, 181(1):145-152). An isobolic experiment ensuesin which the drugs are combined in fractions of their EDXXs to add up toED100 (e.g., ED50:ED50 or ED25:ED75). The plot of the data isconstructed. The experiment points that lie below the straight linebetween the ED50 points on the graph are indicative of synergy, pointson the line are indicative of additive effects, and points above theline are indicative of inhibitory effects. The point of maximumdeviation from the isobolic line is the optimal ratio. This is theoptimal steady state ratio (Cratio,ss) and is adjusted based upon theagents half-life. Similar protocols may be applied in a wide variety ofvalidated animal models.

Example 2 Combinations of an NMDAr Antagonist and an ACheI

Representative combination ranges and ratios are provided below forcompositions of the invention. The ranges given in Table 3 are based onthe formulation strategies described herein.

TABLE 3 Adult Dosage and Ratios for Combination Therapy AcheI Quantity,mg/day/ACheI:NMDA Ratio Range) NMDA drug Donepezil/ Rivastigmine/Galantmine/ Tacrine/ mg/day ARICEPT ® EXELON ® REMINYL ® COGNEX ®Huperzine-A Metrifonate Memantine/ 1-20 1-24 3-48 8-160 0.02-0.8 8-802.5-80 (0.012-8)    (0.012-9.6)   (0.038-19)    (0.1-64)  (0.0025-0.32)  (0.1-32)   Amantadine/ 1-20 1-24 3-48 8-160 0.02-0.8 8-8050-400 (0.0025-0.4)   (0.0025-0.48)   (0.0075-0.96)   (0.02-3.2)  (0.0005-0.016) (0.02-1.6)  Rimantadine/ 1-20 1-24 3-48 8-160 0.02-0.88-80 50-200 (0.005-0.4)   (0.005-0.48)  (0.015-0.96)  (0.04-3.2)  (0.0001-0.016) (0.04-1.6) 

Example 3 Release Profile of Memantine and Galantamine

Release proportions are shown in Table 4 below for a combination ofmemantine and galantamine. The cumulative fraction is the amount of drugsubstance released from the formulation matrix to the serum or gutenvironment (e.g., U.S. Pat. No. 4,839,177) or as measured with a USP IIPaddle system using water as the dissolution medium.

TABLE 4 Release profile of memantine and donepezil MEMANTINE GALANTAMINET1/2 = 60 hrs T1/2 = 7 hrs Time cum. fraction A cum. fraction B 1 0.20.2 2 0.3 0.3 4 0.4 0.4 8 0.5 0.5 12 0.6 0.6 16 0.7 0.7 20 0.8 0.8 240.9 1.0

Example 4 Tablet Containing a Combination of Memantine and Galantamine

An extended release dosage form for administration of memantine andgalantamine is prepared as three individual compartments. Threeindividual compressed tablets are prepared, each having a differentrelease profile, are encapsulated into a gelatin capsule which is thenclosed and sealed. The components of the three tablets are as follows.

TABLE 5 Immediate Release Dosage form Component Function Amount pertablet TABLET 1 (immediate release): Memantine Active agent    0 mgGalantamine HBr Active agent 10.25 mg Dicalcium phosphate dihydrateDiluent  26.6 mg Microcrystalline cellulose Diluent  26.6 mg Sodiumstarch glycolate Disintegrant  1.2 mg Magnesium Stearate Lubricant  0.6mg

TABLE 6 Delayed Release (3-5 hours) Dosage form Component FunctionAmount per tablet TABLET 2 (3-5 hour release): Memantine Active agent  10 mg Galantamine HBr Active agent 10.25 mg Dicalcium phosphatedihydrate Diluent  26.6 mg Microcrystalline cellulose Diluent  26.6 mgSodium starch glycolate Disintegrant  1.2 mg Magnesium StearateLubricant  0.6 mg Eudragit RS30D Delayed release  4.76 mg Talc Coatingcomponent  3.3 mg Triethyl citrate Coating component  0.95 mg

TABLE 7 Delayed Release (7-10 hours) Dosage form Component FunctionAmount per tablet TABLET 3 (Release delayed 7-10 hours): MemantineActive agent  12.5 mg Galantamine HBr Active agent 5.125 mg Dicalciumphosphate dihydrate Diluent  26.6 mg Microcrystalline cellulose Diluent 26.6 mg Sodium starch glycolate Disintegrant  1.2 mg Magnesium StearateLubricant  0.6 mg Eudragit RS30D Delayed release  6.5 mg Talc Coatingcomponent  4.4 mg Triethyl citrate Coating component  1.27 mg

The tablets are prepared by wet granulation of the individual drugparticles and other core components as may be done using a fluid-bedgranulator, or are prepared by direct compression of the admixture ofcomponents. Tablet 1 (Table 5) is an immediate release dosage form,releasing the active agents within 1-2 hours following administration.It contains no memantine to avoid the dC/dT effects of the currentdosage forms. Tablets 2 (Table 6) and 3 (Table 7) are coated with thedelayed release coating material as may be carried out usingconventional coating techniques such as spray-coating or the like. Thespecific components listed in the above tables may be replaced withother functionally equivalent components, e.g., diluents, binders,lubricants, fillers, coatings, and the like.

Oral administration of the capsule to a patient will result in a releaseprofile having three pulses, with initial release of galantamine fromthe first tablet being substantially immediate, release of the memantineand galantamine from the second tablet occurring 3-5 hours followingadministration, and release of the memantine and galantamine from thethird tablet occurring 7-10 hours following administration.

Example 5 Pellets Containing Memantine or Donepezil

Memantine HCl (or Donepezil HCl) containing pellets were prepared by wetmassing. Memantine HCl (or Donepezil HCl) was weighed and sieved througha No. 20 screen into the bowl of low shear planetary mixer. To this,microcrystalline cellulose was weighed and added through No. 20 screenand blended with Memantine HCl (or Donepezil HCl) using a spatula, thenin a planetary mixer on low speed. Eudragit NE 400, accurately weighedwas incrementally added to the powder blend, allowing sufficient timebetween additions for complete distribution. To avoid accumulation atthe bottom and to loosen the material, the bottom was periodicallyscraped. Purified water was blended into the mixture in 10 mL increments(the first of which was used to rinse the beaker containing Eudragit NE40D) until a uniform blend appropriate for extrusion was obtained.Experimental batches were prepared with 10 to 50 ml water. Wet massingwas followed by extrusion, spheronization and drying by procedures wellknown in the prior art.

TABLE 8 Pellets containing Memantine HCl Percent Wt. solid Target Actualin per Batch Wt. per Wt. per Component Supplier Formula¹ (grams) Batch(g) Batch (g) Memantine HCl  20.0%  50.0  50.0  50.00 Eudragit NE 40DDegussa  30.0%  75.0 187.5 187.50 Microcrystalline FMC  50.0% 125.0125.0 125.00 Cellulose Corp (Avicel PH 101) Purified Water N/A N/A  50.010.0 TOTAL 100.0% 250.0 N/A N/A ¹based on solid in the final product

TABLE 9 Pellets containing Donepezil HCl Percent Wt. solid Target Actualin per Batch Wt. per Wt. per Component Supplier Formula¹ (grams) Batch(g) Batch (g) Donepezil HCl  20.0%  40.0  40.0  39.98 Eudragit NE 40DDegussa  30.0%  60.0 150.0 150.05 Microcrystalline FMC  50.0% 100.0100.0 100.00 Cellulose Corp (Avicel PH 101) Purified Water N/A N/A  50.010.0 TOTAL 100.0% 200.0 N/A N/A ¹based on solid in the final product

Example 6 Memantine HCl/Donepezil HCl Formulations

Formulations of Sustained Release (SR) Memantine HCl (or Donepezil HCl),fast and medium, were obtained by applying a subcoat of Opadry (2% finalpellet weight) followed by a functional coating of Surelease (15%dispersion prepared from 25% Surelease) to 20% Memantine HCl (orDonepezil HCl) pellets.

Formulations of Sustained Release (SR) Memantine HCl (or Donepezil HCl),slow, were obtained by applying a subcoat of Opadry (10% final beadweight), functional coating of plasticized Eudragit RS (35% final pelletweight) and triethylcitrate (plasticizer, 10% of the functional coating)to 20% Memantine HCl (or Donepezil HCl) pellets.

TABLE 10 Memantine SR Products SR SR Memantine SR Memantine PelletsMemantine Product Pellets (Fast) (Medium) Pellets (Slow) “Label Claim”0.164 Blend 0.100 (mg active/ of 40% mg pellets) “Fast” and Sampleweight 134.6 136.2 60% 207.9 208.9 (mg pellets) “Slow” 16 hr “Assay”23.41 23.44 17.97 18.24 Value (mg released) “Assay” Value 0.174 0.1720.0864 0.0873 (mg active/ mg pellets) Average Assay 0.173 0.0869 Value(mg active/ mg pellets) Amount of 130.0 52.0 155.4 259.0 pellets for22.5 mg dose (mg)

TABLE 11 Donepezil Immediate Release (IR) Product Product IR DonepezilHCl “Label Claim” (mg active/mg granulation) 0.0357 Sample weight (mgpellets) 140.6 143.7 “Assay” Value (mg released) 4.25 4.28 “Assay” Value(mg active/mg granulation) 0.0302 0.0298 Average Assay Value (mgactive/mg gran) 0.030 Amount of granulation for 5 mg dose (mg) 166.7

TABLE 12 Donepezil SR Product Product SR Donepezil SR Donepezil SRDonepezil HCl Pellets HCl Pellets HCl Pellets (Fast) (Medium) (Slow)“Label Claim” 0.180 0.166 0.156 (mg active/ mg pellets) Sample weight113.8 113.9 135.6 135.5 128.8 128.3 (mg pellets) 16 hr “Assay” 20.0320.00 23.26 23.46 19.27 19.86 Value (mg released) “Assay” Value 0.1760.176 0.172 0.173 0.150 0.155 (mg active/ mg pellets) Average Assay0.176 0.172 0.152 Value (mg active/ mg pellets) Amount of 28.4 29.0 32.8pellets for 5 mg dose (mg)

Example 7 Dosage Formulation of Memantine-Donepezil Combination

Various combinations of memantine and donepezil were prepared by fillingthe respective pellets in hard gelatin capsules as shown in Table 13.The separately prepared pellets provide the flexibility of making ratiosof memantine to donepezil pellets ranging from 0.1:100 to 100:0.1, morepreferably from 1:100 to 100:1, most preferably 1:10 to 10:1.

TABLE 13 Memantine-Donepezil Dosage Combinations Memantine Donepezil Wt.solid/ Wt. solid/ dosage Unit dosage Unit Product (in mg) Formulation(in mg) Formulation NPI-6170 130.0 SR (Fast) 166.7 IR NPI-6270 52.0 SR(Fast) 166.7 IR 155.4 SR (Slow) NPI-6370 259.0 SR (Slow) 166.7 IRNPI-6171 130.0 SR (Fast) 28.4 SR (Fast) NPI-6271 52.0 SR (Fast) 28.4 SR(Fast) 155.4 SR (Slow) NPI-6371 259.0 SR (Slow) 28.4 SR (Fast) NPI-6172130.0 SR (Fast) 29.0 SR (medium) NPI-6272 52.0 SR (Fast) 29.0 SR(medium) 155.4 SR (Slow) NPI-6372 259.0 SR (Slow) 29.0 SR (medium)NPI-6173 130.0 SR (Fast) 32.8 SR (Slow) NPI-6273 52.0 SR (Fast) 32.8 SR(Slow) 155.4 SR (Slow) NPI-6373 259.0 SR (Slow) 32.8 SR (Slow) SR =Sustained Release, IR = Immediate Release

Example 8 Dissolution Profiles

The dissolution profiles of the various memantine-donepezil combinations(as shown in Example 7) were obtained from USP II (paddle) dissolutionsystem at 50 rpm, at a temperature of 37.0±0.5° C., using water as themedium (FIGS. 2A-2C, 3A-3C, 4A-4C and 5A-5C).

For the dissolution analysis, 10 mL dissolution solutions of memantineand donepezil were diluted with 3 mL of 0.1% formic acid. Standards ofmemantine or donepezil were also prepared and diluted with 3 mL of 0.1%formic acid. A 1 mL aliquot of the diluted solution or standard wastransferred into an HPLC vial. A 10 μL aliquot of the solution orstandard was injected onto the LC/MS/MS for analysis. A C18 reversedphase column (Phenomenex, Luna 5μ, Phenyl-Hexyl 50×2 mm) was used foranalysis. Memantine and donepezil were separated from endogenousinterfering substances and subsequently eluted from the HPLC column by amobile phase of 33% acetonitrile, 33% methanol and 34% formic acid formass quantification. A mass spectrometer set at mass-to-charge ratios(m/z) of 180.51>162.70 and 380.14>288.18 was used to detect and quantifymemantine and donepezil, respectively. Data were processed andcalculated by an automated data acquisition system (Analyst 1.2, AppliedBiosystems, Foster City, Calif.).

Example 9 Release Profiles of IR and SR Memantine-Donepezil Formulations

The in vivo release profiles were obtained using the Gastro-Plussoftware package v.4.0.2 (FIGS. 6A-6E, 7). Exemplary human PK releaseprofiles are shown in FIG. 7. The release profiles and pharmacokineticproperties for a controlled release combination product made accordingto Examples 5-7 as compared to IR administration of presently marketedproducts are shown in FIG. 7 and the table in FIG. 8. For the IRadministration, oral dosing is per the manufacturers' recommendation (5mg memantine q.d., incremented on a weekly basis to 5 mg BID, 10 mg inthe morning and 5 mg in the evening, and 10 mg memantine b.i.d.thereafter; 5 mg donepezil q.d. for two weeks, increasing to 10 mgdonepezil q.d. thereafter). For the SR formulation NPI-6272, the 22.5 mgmemantine and 10 mg donepezil are provided in a controlled release oraldelivery formulation releasing the active agents as shown in FIG. 4B.The SR product dC/dT is considerably lower than the IR form for asimilar dose for both memantine and donepezil. As measured, the dC/dTfor memantine at 22.5 mg is comparable to that for a 5 mg IR dosageform. Thus, the SR formulations provide a more gradual increase in thedrug during each patient dose.

In addition to achieving the desired release profile, this combinationformulation will exhibit a preferred decrease Cmax/Cmean, even with ahigher dose of the NMDAr antagonist and ACheI, thus the presentinvention may provide greater doses for increased therapeutic effectwithout escalation that might otherwise be required. Furthermore, theincreased dosing allows less frequent administration of the therapeuticagents.

Example 10 A Patch Providing Extended Release of Memantine andRivastigmine

As described above, extended release formulations of an NMDAr antagonistare formulated for topical administration. Memantine transdermal patchformulations are prepared as described, for example, in U.S. Pat. Nos.6,770,295 and 6,746,689.

For the preparation of a drug-in-adhesive acrylate, 5 g of memantine and1 g of rivastigmine are dissolved in 10 g of ethanol and this mixture isadded to 20 g of Durotak 387-2287 (National Starch & Chemical, U.S.A.).The drug gel is coated onto a backing membrane (Scotchpak 1012; 3MCorp., U.S.A.) using a coating equipment (e.g., RK Print Coat Instr.Ltd, Type KCC 202 control coater). The wet layer thickness is 400 μm.The laminate is dried for 20 minutes at room temperature and then for 30minutes at 40° C. A polyester release liner is laminated onto the drieddrug gel. The sheet is cut into patches and stored at 2-8° C. until use(packed in pouches). The concentration of memantine in the patchesranges between 5.6 and 8 mg/cm², while rivastigmine ranges between 1.1and 1.6 mg/cm². The nearly continuous infusion of the componentsprovides a much more consistent Cratio over time maximizing the additiveor synergistic effects of the combinations of the present invention toachieve the optimal therapeutic effects.

Example 11 Multiple Dose Safety Study in Alzheimer's Patients with anExtended Release Memantine, Extended Release Donepezil Combination

A study to determine safety and pharmacokinetics of an extended releasecombination formulation of memantine and donepezil is described below.The study results are expected to assess the frequency of adverse eventsas well as evaluate the pharmacokinetic parameters at higher doses.

Purpose To determine the safety and pharmacokinetics of repeated dosesof drug. Dosage: Based on previous single ascending dose (SAD) study,either e.g. 22.5 mg memantine SR + 4 mg donepezil SR, 45 mg memantineSR + 4 mg donepezil SR, or 45 mg memantine SR + 8 mg donepezil SR, QDfor 30 days Concurrent Controls memantine IR or memantine IR plusdonepezil IR (both dosed as per manufacturers' labels) Route: OralSubject Population: Males or females diagnosed with dementia of theAlzheimer's type. (Age range 50-80?) Structure: 4 arm Study Sites: TBDBlinding: Patients blinded Method of Subject Random with equal number ofmales Assignment: and females in each group and equal age distributionswithin groups Total Sample Size: 24 Subjects 6 per dosing arm PrimaryEfficacy Endpoint: None Adverse Events: Monitored at least twice dailyfor behavioral, cardiovascular, and gastrointestinal effects reportedfor high doses of memantine or donepezil (including dizziness, headache,confusion, constipation, hypertension, coughing, nausea, diarrhea,vomiting). Blood Collection By canula through first day of study periodthen 2-4 times daily for rest of study Analysis Assays to measurememantine, donepezil, and potentially other physiological parameters,adverse events

Example 12 Treatment of Alzheimer's Patients with an Extended ReleaseMemantine, Extended Release Donepezil Combination

A study to determine effectiveness of two extended release combinationformulations of memantine and donepezil is described below. The studyresults are expected to establish a more rapid onset of efficacy withoutincrease in adverse effects (confirming tolerability of a non-doseescalating dosing regimen (i.e., administration of substantiallyidentical doses of memantine and donepezil throughout the term ofdosing)).

Purpose To determine the efficacy of combination therapy, non-doseescalated Study Dosages: 22.5 mg memantine SR + 4 mg donepezil SR, 45 mgmemantine SR + 4 mg donepezil SR Concurrent Controls memantine IR(Namenda) or memantine IR plus donepezil IR (Aricept) both permanufacturers' dosing labels (as of 2004). Route: Oral SubjectPopulation: Males or females diagnosed with dementia of the Alzheimer'stype. (Age range 50-80) Structure: 4 arm Study Sites: Multi-centerBlinding: Patients blinded Method of Subject Random with equal number ofmales and females in Assignment: each group and equal age distributionswithin groups Total Sample Size: 400 subjects, 100 per arm PrimaryEfficacy Improvement of ADAS-Cog, SIBIC, HAM-D in or Endpoint:neuropsychiatric index at 7, 14, 21, 42, 63, 84 days. EfficacyMonitoring: Monitored twice per week for first 4 weeks, then weeklythereafter. Adverse Events: Monitored at least twice daily forbehavioral, cardiovascular and gastrointestinal effects reported forhigh doses of memantine or donepezil (including dizziness, headache,confusion, constipation, hypertension, coughing, nausea, diarrhea,vomiting). Blood Collection: By canula at the following time points: Day1: 0, 4, 8, 12 hours Days 2, 4, 6, 8, 10, 12, 14, 17, 21, 28, 35, 42,49, 56, 63, 70, 77, 84 pre-dose trough Analysis: Efficacy, adverseevents, and laboratory assays measuring study drugs.

What is claimed is:
 1. A method of treating a patient with aneurological condition, comprising orally administering to a humansubject in need thereof: (a) 22.5 mg to 30 mg memantine or apharmaceutically acceptable salt thereof provided in a sustained releasedosage form, wherein said sustained release memantine provides a changein mean plasma concentration of memantine as a function of time (dC/dT)that is: (1) less than about 50% of the dC/dT provided by the samequantity of an immediate release form of memantine, determined in a timeperiod between 0-Tmax of the immediate release form of memantine; and(2) 2.1 ng/ml/hr or less, determined in a time period of 0 to 4 hours;wherein dC/dT is measured in a single-dose human PK study; and (b) atherapeutically effective amount of immediate release donepezil.
 2. Themethod of claim 1, wherein the dC/dT of 2.1 ng/mL/hr or less isdetermined in a time period of 2 to 4 hours.
 3. The method of claim 1,wherein the neurological condition is selected from the group consistingof Alzheimer's disease, dementia, Parkinson's disease, and neuropathicpain.
 4. The method of claim 3, wherein the dC/dT of 2.1 ng/mL/hr orless is determined in a time period of 2 to 4 hours.
 5. The method ofclaim 1, wherein the sustained release oral dosage form comprises 25 mgto 30 mg memantine or a pharmaceutically acceptable salt thereof.
 6. Themethod of claim 5, wherein the dC/dT of 2.1 ng/mL/hr or less isdetermined in a time period of 2 to 4 hours.
 7. The method of claim 6,wherein the neurological condition is selected from the group consistingof Alzheimer's disease, dementia, Parkinson's disease, and neuropathicpain.
 8. The method of claim 5, wherein the neurological condition isselected from the group consisting of Alzheimer's disease, dementia,Parkinson's disease, and neuropathic pain.
 9. The method of claim 1,wherein the sustained release oral dosage form comprises 28 mg memantineor a pharmaceutically acceptable salt thereof.
 10. The method of claim9, wherein the dC/dT of 2.1 ng/mL/hr or less is determined in a timeperiod of 2 to 4 hours.